Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stress

• Published in: Genes & development 1998-07, Vol.12 (13), p.1941-1946
• Main Authors: Zundel, W, Giaccia, A
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - radiation effects; bcl-Associated Death Protein; Carrier Proteins - antagonists & inhibitors; Cell Line; Cell Line, Transformed; Ceramides - pharmacology; Down-Regulation - drug effects; Down-Regulation - radiation effects; Enzyme Activation - drug effects; Enzyme Activation - radiation effects; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - radiation effects; Gamma Rays; Humans; Phosphatidylinositol 3-Kinases - radiation effects; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins c-akt; Rats; Research Communication; Signal Transduction - drug effects; Signal Transduction - physiology; Signal Transduction - radiation effects; Stress, Physiological - enzymology; Stress, Physiological - pathology; Ultraviolet Rays
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.12.13.1941

The initiation of apoptosis often transpires in the presence of agents that regulate cell survival. This study evaluated the effects of stress-induced ceramide on the anti-apoptotic activity of the phosphoinositide-3 kinase [PI(3)K] pathway. PI(3)K activity is directly down-regulated by stress-induced ceramide in a dose-dependent manner with rapid kinetics and high specificity. Ceramide inhibition of PI(3)K is dependent on acid-sphingomyelinase. Down-regulation of PI(3)K by ceramide results in inhibition of the kinase Akt and decreased phosphorylation of the death effector Bad. Thus, ceramide levels could act as a general apoptotic rheostat controlling cell survival by regulating PI(3)K anti-apoptotic effector mechanisms.